Lamotrigine is known as 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine or 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine. The molecular formula of lamotrigine is C9H7N5Cl2, and its molecular weight is 256.09 g/mol. Lamotrigine is depicted by the following chemical structure:
Lamotrigine is the active ingredient in Lamictal® marketed by GlaxoSmithKline. It is an anti-convulsant drug of the phenyltriazine class used in the treatment of epilepsy as well as in the treatment of psychiatric disorders such as bipolar disorder. Lamotrigine is indicated for the adjunctive treatment of partial and primary generalized tonic-clonic seizures and generalized seizures associated with Lennox-Gastaud syndrome. Lamotrigine is indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with anti-epileptic drugs carbamazepine, phenyloin, phenobarbital, primidone or valproate. Lamotrigine also acts as a mood stabilizer. Lamotrigine is also useful for the treatment of neuropathic pain, cluster headaches, migraines and affective disorders.
Lamotrigine is available as a compressed tablet and as a chewable dispersible tablet for oral administration. The chewable dispersible tablets can be swallowed, chewed, or dispersed in a small amount of liquid to form slurry. This formulation was developed to facilitate administration to mainly people with swallowing difficulties such as children and elderly patients.
The peak plasma concentrations of the existing marketed tablet occur anywhere from 1.4 to 4.8 hours following drug administration. One disadvantage of this is that the plasma concentration (pharmacokinetic profile (PK)) achieved with conventional tablets is cyclical, with relatively high peaks occurring after administration followed by low troughs occurring before the next administration of drug.
In particular for the treatment of epilepsy it is thought that too-low troughs in the peak plasma concentration may lead to breakthrough seizures, result in some adverse events (AE) occurring in some patients. Alternatively, a too-rapid rate of increase in plasma concentration in the initial stages before the peak plasma concentration is achieved may also affect the AE profile.
Until recently, it was not known where, in the gastrointestinal tract, lamotrigine is absorbed (U.S. Appl. Publ. No. 2005/0032799). In carrying out a regional absorption study it has recently been discovered that the extent of absorption of lamotrigine is consistent when the drug is delivered to any point in the gastrointestinal tract between the stomach and the ascending colon. The extent of absorption is similar whether the drug is delivered as a solid or as a solution.
Preparation of Lamotrigine and its Therapeutic Uses are Disclosed in U.S. Pat. No. 4,602,017.
Different synthetic methods of lamotrigine are described in WO 01/049669, U.S. Pat. Nos. 6,111,101, 6,333,198, 5,912,345, and EP 800521.
Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25° C.) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25° C.).
Lamotrigine benzoate dimethylformamide solvate (Sridhar et al., Acta Cryst. (2005) E61, o-3805) and lamotrigine hydrogen phthalate dimethylformamide solvate (Sridhar et al., Mol. Cryst. Liq. Cryst. (2007) 461, 131) have been reported.
Various patents and references have attempted to solve use limitations caused by lamotrigine's poor solubility. See, e.g., U.S. Appl. Publ. No. 2005/0119265; Kubicki and Codding (J. Mol. Struct. (2001) 570, 53; WO 02/068398; EP 0,247,892; U.S. Pat. Nos. 5,912,345; 5,925,755; 4,847,249; and 5,942,510. In general, these approaches have involved different crystal forms, different salt forms, or reducing particle size. Some formulation approaches in the foregoing, particularly those involving certain salt forms, are undesirable for particular uses, such as parenteral, owing to their inherent lack of stability or acidity.
Because of the limitations related to the low aqueous solubility of lamotrigine, there is a need to develop novel forms of lamotrigine that have improved physico-chemical properties including aqueous solubility, which can be formulated for use in various delivery routes, including parenteral and oral administration.